Substituted 1-aryl-3-heteroaryl-thioureas and substituted 1-aryl-3-heteroaryl-isothioureas as antiatherosclerotic agents

ABSTRACT

Antiatherosclerotic agents are provided which are represented by Formulas I or II:                    
     wherein 
     R is                    
     wherein R 9 , R 10 , R 11 , R 12 , R 13 , and R 14  are each, independently, hydrogen or a lower alkyl of 1-6 carbon atoms; 
     R 6 , and R 7  are each, independently, hydrogen, lower alkyl of 1-6 carbon atoms, or CH 2 COOR 8 , where R 8  is a lower alkyl of 1-6 carbon atoms; and 
     X is O or S; 
     R 1  is hydrogen or a lower alkyl of 1-6 carbon atoms; 
     R 2 , R 3 , and R 4  are each, independently, hydrogen or halogen; and 
     R 5  is a lower alkyl of 1-6 carbon atoms; 
     or a pharmaceutically acceptable salt thereof.

“This application claims priority from application Ser. No. 09/145,909filed Sep. 2, 1998, now U.S. Pat. No. 6,455,566 B1, the entiredisclosure of which is hereby incorporated by reference.”

FIELD OF THE INVENTION

This invention is directed to antiatherosclerotic agents and morespecifically to compounds, compositions and methods useful for elevatingHDL cholesterol concentration which may be useful in the treatment ofatherosclerosis and related conditions, such as dyslipoproteinemias andcoronary heart disease.

BACKGROUND OF THE INVENTION

Numerous studies have demonstrated that both the risk of coronary heartdisease (CHD) in humans and the severity of experimental atherosclerosisin animals are inversely correlated with serum HDL cholesterol (HDL—C)concentrations (Russ et al., Am. J. Med., 11 (1951) 480-483; Gofman etal. Circulation, 34 (1966), 679-697; Miller and Miller, Lancet, 1(1975), 16-19; Gordon et al., Circulation, 79 (1989), 8-15; Stampfer etal., N. Engl. J. Med., 325 (1991), 373-381; Badimon et al., Lab.Invest., 60 (1989), 455-461). Atherosclerosis is the process ofaccumulation of cholesterol within the arterial wall which results inthe occlusion, or stenosis, of coronary and cerebral arterial vesselsand subsequent myocardial infarction and stroke. Angiographic studieshave shown that elevated levels of some HDL particles in humans appearto be correlated to a decreased number of sites of stenosis in thecoronary arteries of humans (Miller et al., Br. Med. J., 282 (1981),1741-1744).

There are several mechanisms by which HDL may protect against theprogression of atherosclerosis. Studies in vitro have shown that HDL iscapable of removing cholesterol from cells (Picardo et al.,Arteriosclerosis, 6 (1986), 434-441). Data of this nature suggest thatone antiatherogenic property of HDL may lie in its ability to depletetissue of excess free cholesterol and eventually lead to the delivery ofthis cholesterol to the liver (Glomset, J. Lipi Res., 9 (1968),155-167). This has been supported by experiments showing efficienttransfer of cholesterol from HDL to the liver (Glass et al., J. Biol.Chem., 258 (1983), 7161-7167; McKinnon et al., J. Biol. Chem., 261(1986), 2548-2552). In addition, HDL may serve as a reservoir in thecirculation for apoproteins necessary for the rapid metabolism oftriglyceride-rich lipoproteins (Grow and Fried, J. Biol. Chem., 253,(1978), 1834-1841; Lagocki and Scanu, J. Biol. Chem., 255 (1980),3701-3706; Schaefer et al., J. Lipid Res., 23 (1982), 1259-1273). Morerecently, as a possible mechanism for protection against the developmentof atherosclerosis, Cockerill et. al. (Arterioscler., Thromb., Vasc.Biol, 15, (1995), 1987-1994) have demonstrated that plasma HDL's inhibitthe cytokine-induced expression of endothelial cell adhesion molecules(VCAM-1 and ICAM-1) in a concentration dependent and cell specificmanner. Accordingly, it is believed that agents which increase HDLcholesterol concentration would be of utility as anti-atheroscleroticagents, useful particularly in the treatment of dyslipoproteinimias andcoronary heart disease.

Ureas, thioureas and derivatives thereof are known to be useful for thetreatment of various conditions. For example, the use of urea andthiourea derivatives as tyrosine kinase inhibitors, to inhibit cellproliferation and differentiation in the treatment of cancer isdisclosed in WO 9640673-A1. The use of [(alkoxy) pyridinyl] aminoderivatives to inhibit the secretion of gastric acid is disclosed inWO-9315055. N-phenyl thiourea derivatives and their use in the treatmentof atherosclerosis is disclosed in CA-2072704. The use of bis-aryl ureasand related compounds as cardiovascular agents is disclosed inCA-2132771, while the administration of ureas and thioureas for thetreatment of ischaemia, asthma, Parkinson's disease, epilepsy, andurinary incontinence is disclosed in U.S. Pat. No. 5,547,966.Substituted thioureas and isothioureas are also disclosed in U.S. Pat.No. 5,185,358.

The treatment of atherosclerosis with certain ureas, thioureas andderivatives thereof has been suggested in Japanese Patent 83-01841 (theuse of ureas and thioureas as inhibitors of squalene epoxidase); U.S.Pat. No. 4,623,662 (the use of certain urea and thiourea compounds tolower serum lipids in warm-blooded animals); and U.S. Pat. Nos.4,387,105 and 4,387,106 (the use of di(aralkyl) ureas and di(aralkyl)thioureas to inhibit fatty acyl CoA: cholesterol acyl transferase).However, the treatment of atherosclerosis, and the relatedcardiovascular disease and dyslipoproteinemias, through the elevation ofserum HDL cholesterol concentrations with the present urea and thioureaderivatives, has heretofore not been recognized.

SUMMARY OF THE INVENTION

The present invention relates to antiatherosclerotic agents comprising1-aryl-3-heteroaryl-thioureas and 1-aryl-3-heteroaryl-isothioureasrepresented by formulas I and II:

wherein

R is

wherein R₉, R₁₀, R₁₁, R₁₂, R₁₃, and R₁₄ are each, independently,hydrogen or a lower alkyl of 1-6 carbon atoms;

R₆, and R₇ are each, independently, hydrogen, lower alkyl of 1-6 carbonatoms, or CH₂COOR₈, where R₈ is a lower alkyl of 1-6 carbon atoms; and

X=O or S;

R₁ is hydrogen or a lower alkyl of 1-6 carbon atoms;

R₂, R₃, and R₄ are each, independently, hydrogen or halogen; and

R₅ is a lower alkyl of 1-6 carbon atoms;

or a pharmaceutically acceptable salt thereof.

The present invention is further directed to methods of elevating theHDL concentration and treating atherosclerosis and related coronaryheart disease and dyslipoproteinemias in a mammal in need thereof,comprising administering to the mammal an effective amount of theantiatherosclerotic agents of formulas I and II:

wherein

R is

wherein R₉, R₁₀, R₁₁, R₁₂, R₁₃, and R₁₄ are each, independently,hydrogen or a lower alkyl of 1-6 carbon atoms;

R₆, and R₇ are each, independently, hydrogen, lower alkyl of 1-6 carbonatoms, or CH₂COOR₈, where R₈ is a lower alkyl of 1-6 carbon atoms; and

X is O or S;

R₁ is hydrogen or a lower alkyl of 1-6 carbon atoms;

R₂, R₃, and R₄ are each, independently, hydrogen or halogen; and

R₅ is a lower alkyl of 1-6 carbon atoms;

or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

Preferably, the antiatherosclerotic agents of the present invention arethose represented by formulas I and II where:

R is

wherein:

R₉, R₁₀, R₁₁, R₁₂, R₁₃, and R₁₄ are each, independently, hydrogen orlower alkyl of 1 to 6 carbon atoms;

R₆ and R₇ are, each independently, lower alkyl of 1 to 6 carbon atoms;and

X is O or S;

R₁ is hydrogen;

R₂, R₃, and R₄ are each, independently, hydrogen or halogen; and

R₅ is a lower alkyl of 1 to 6 carbon atoms;

or a pharmaceutically acceptable salt thereof.

As used in this invention, the term “lower alkyl” includes both straightchain as well as branched moieties. The terms “halo” or “halogen”includes fluorine, chlorine, bromine, and iodine.

The compounds of Formula I are known to be unstable to salt formation.Accordingly, the expression “pharmaceutically acceptable salts” as usedherein should be construed as applying only to the compounds of FormulaII. The pharmaceutically acceptable salts of the present compoundsinclude those derived from organic and inorganic acids, including, butnot limited to, acetic, lactic, citric, tartaric, succinic, fumaric,maleic, malonic, malic, hydrochloric, hydrobromic, phosphoric, nitric,sulfuric, methane sulfonic, toluene sulfonic and similarly knownacceptable acids.

The most preferred compounds according to this invention are:

1-(5-Chloro-2-methyl-phenyl)-3-(thiazol-2-yl)-thiourea;

1-(5-Chloro-2-methyl-phenyl)-3-(4-methyl-oxazol-2-yl)-thiourea;

1-(5-Chloro-2-methyl-phenyl)-3-(5-methyl-[1,3,4]thiadiazol-2-yl)-thiourea;

1-(5-Chloro-2-methyl-phenyl)-3-(1H-pyrazol-3-yl)-thiourea;

1-(5-Chloro-2-methyl-phenyl)-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-thiourea;

1-(5-Chloro-2-methyl-phenyl)-3-(4-methyl-thiazol-2-yl)-thiourea;

1-(5-Chloro-2-methyl-phenyl)-3-(4,5-dimethyl-thiazol-2-yl)-thiourea;

1-(5-Chloro-2-methyl-phenyl)-3-(3-methyl-isothiazol-5-yl)-thiourea;

1-(5-Chloro-2-methyl-phenyl)-3-(2-methyl-benzothiazolyl-5-yl)-thiourea;

1-(5-Chloro-2-methyl-phenyl)-3-(5-ethyl-[1,3,4]thiadiazol-2-yl)-thiourea;

1-(2-Chloro-6-methyl-phenyl)-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-thiourea;

1-(4-Chloro-2-methyl-phenyl)-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-thiourea;

1-(4-Chloro-2-methyl-phenyl)-3-(4-methyl-oxazol-2-yl)-thiourea;

1-(2-Chloro-6-methyl-phenyl)-3-(4-methyl-oxazol-2-yl)-thiourea;

3-(5-Chloro-2-methyl-phenyl)-1-ethyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-thiourea;

(E)-1-(5-Chloro-2-methyl-phenyl)-2-methyl-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-isothiourea;and

3-(5-Chloro-2-methyl-phenyl)-1-ethyl-2-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-isothiourea.

The 1-aryl-3-heteroaryl-thioureas of the present invention may beprepared by the reaction of an appropriately substitutedaryl-isothiocyanate with a substituted amino heterocycle (see, e.g., J.March, Advanced Organic Chemistry, 3rd Ed., Wiley-Interscience, N.Y.,page 802) as shown in scheme 1

wherein R, R₁, R₂, R₃, and R₄ are as described above for formula I.

The substituted heterocyclic amine starting materials are eithercommercially available, known in the art or can be prepared byprocedures analogous to those in the literature for known heterocycles(see Katritzky, Handbook of Heterocyclic Chemistry, Pergamon Press,N.Y., 416-428 and 468-469, (1985)). Primary heterocyclic amines can befunctionalized to secondary amines in a manner known to those skilled inthe art, such as described below in Example 21.

The appropriately substituted aryl isothiocyanates starting materialsare either commercially available, known in the art or can be preparedby procedures analogous to those in the literature.

The substituted 1-aryl-3-heteroaryl-isothioureas of the presentinvention may be prepared from 1-aryl-3-heteroaryl-thioureas underS-alkylating conditions as described e.g., in Rassmussen, C. R. et al,Synthesis 460, (1988) as shown scheme 2:

wherein R, R₁, R₂, R₃, R₄ and R₅ are as described above for formula II.

Representative compounds according to the present invention wereevaluated in an in vivo standard pharmacological test procedure whichmeasured the ability of the compounds to elevate HDL cholesterol levels.The following describes the procedure used and results obtained. MaleSprague-Dawley rats weighing 200-225 g were housed two per cage and fedPurina Rodent Chow Special Mix 5001-S supplemented with 0.25% cholicacid and 1.0% cholesterol and water ad libitum for 8 days. Each testsubstance was administered to a group of six rats fed the same diet withthe test diet mixed in as 0.005-0.1% of the total diet. Body weight andfood consumption were recorded prior to diet administration and attermination. The test substances were administered at a dosage of 100mg/kg/day.

At termination, blood was collected from anesthetized rats and the serumwas separated by centrifugation. Total serum cholesterol was assayedusing the Sigma Diagnostics enzymatic kit for the determination ofcholesterol, Procedure No. 352, modified for use with ninety-six wellmicrotiter plates. After reconstitution with water the reagent contains300 U/l cholesterol oxidase, 100 U/l cholesterol esterase, 1000 U/lhorse radish peroxidase, 0.3 mmoles/l 4-aminoantipyrine and 30.0mmoles/l p-hydroxybenzene sulfonate in a pH 6.5 buffer. In the reaction,cholesterol was oxidized to produce hydrogen peroxide which was used toform a quinoneimine dye. The concentration of dye formed was measuredspectrophotometrically by absorbance at 490 nm after incubation at 25°C. for 30 minutes. The concentration of cholesterol was determined foreach serum sample relative to a commercial standard from Sigma.

HDL cholesterol concentrations in serum were determined by separation oflipoprotein classes by fast protein liquid chromatography (FPLC) by amodification of the method of Kieft et al., J. Lipid Res., 32 (1991),859-866. Using this methodology, 25 mL of serum was injected ontoSuperose 12 and Superose 6 (available from Pharmacia), in series, with acolumn buffer of 0.05 M Tris (2-amino-2-hydroxymethyl-1,3-propanediol)and 0.15 M sodium chloride at a flow rate of 0.5 mL/min. The elutedsample was mixed on line with Boehringer-Mannheim cholesterol reagentpumped at 0.2 mL/min. The combined eluents were mixed and incubated online through a knitted coil (available from Applied Biosciences)maintained at a temperature of 45° C. The eluent was monitored bymeasuring absorbance at 490 nm and gave a continous absorbance signalproportional to the cholesterol concentration. The relativeconcentration for each lipoprotein class was calculated as the percentof total absorbance. HDL cholesterol concentration in serum, wascalculated as the percent of total cholesterol as determined by FPLCmultiplied by the total serum cholesterol concentration.

Test compounds were administered at a dose of 100 mg/kg for 8 days. Theincrease in serum concentrations of HDL cholesterol are summarized inTable 1.

TABLE 1 Example Number HDL Cholesterol Level Increase (%) 1 65 2 6 3 0.34 158 5 69 6 −11 7 97 8 110 9 79 10 41 11 2 12 134 13 36 14 90 15 58 16104 17 134 18 193 19 79 20 35 21 29

The results set forth in Table I demonstrate that the compounds of thepresent invention are useful in raising the concentration of HDLcholesterol, and are therefore, useful for treating or inhibitingatherosclerosis, related cardiovascular disease, or dyslipoproteinemias,and for improving the HDL/LDL cholesterol ratio. Moreover, in light oftheir ability to elevate HDL cholesterol concentrations, the presentcompounds are useful in treating several metabolic conditions associatedwith low concentrations of HDL, such as low HDL-cholesterol levels inthe absence of dyslipidemia, metabolic syndrome, non-insulin dependentdiabetes mellitus (NIDDM), familial combined hyperlipidemia, familialhypertriglyceridemia, and dyslipidemia in peripheral vascular disease(PVD).

The compounds of this invention may be administered orally orparenterally, neat or in combination with conventional pharmaceuticalcarriers. Applicable solid carriers can include one or more substanceswhich may also act as flavoring agents, lubricants, solubilizers,suspending agents, fillers, glidants, compression aids, binders ortablet-disintegrating agents or an encapsulating material. In powders,the carrier is a finely divided solid which is in admixture with thefinely divided active ingredient. In tablets, the active ingredient ismixed with a carrier having the necessary compression properties insuitable proportions and compacted in the shape and size desired. Thepowders and tablets preferably contain up to 99% of the activeingredient. Suitable solid carriers include, for example, calciumphosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch,gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidone, low melting waxes and ion exchange resins.

Liquid carriers may be used in preparing solutions, suspensions,emulsions, syrups and elixirs. The compounds of the present inventioncan be dissolved or suspended in a pharmaceutically acceptable liquidcarrier such as water, an organic solvent, a mixture of both orpharmaceutically acceptable oils or fat. The liquid carrier can containother suitable pharmaceutical additives such as solubilizers,emulsifiers, buffers, preservatives, sweeteners, flavoring agents,suspending agents, thickening agents, colors, viscosity regulators,stabilizers or osmo-regulators. Suitable examples of liquid carriers fororal and parenteral administration include, water (particularlycontaining additives as above e.g. cellulose derivatives, preferablysodium carboxymethyl cellulose solution), alcohols (including monohydricalcohols and polyhydric alcohols e.g. glycols) and their derivatives andoils (e.g. fractionated coconut oil and arachis oil). For parenteraladministration, the carrier can also be an oily ester such as ethyloleate and isopropyl myristate. Sterile liquid carriers are used insterile liquid form compositions for parenteral administration.

Liquid pharmaceutical compositions which are sterile solutions orsuspensions can be utilized by, for example, intramuscular,intraperitoneal or subcutaneous injection. Sterile solutions can also beadministered intravenously. Compositions for oral administration may beeither liquid or solid composition form.

Preferably, the pharmaceutical compositions containing the presentcompounds are in unit dosage form, e.g. as tablets or capsules. In suchform, the compositions are sub-divided in unit doses containingappropriate quantities of the active ingredient. The unit dosage formscan be packaged compositions, for example packeted powders, vials,ampoules, prefilled syringes or sachets containing liquids. The unitdosage form may also be, for example, a capsule or tablet itself, or itcan be the appropriate number of any such compositions in package form.

The therapeutically effective amount of the compounds of this inventionthat is administered and the dosage regimen depends on a variety offactors, including the weight, age, sex, medical condition of thesubject, the severity of the disease, the route and frequency ofadministration, and the specific compound employed, and thus may varywidely. However, it is believed that the pharmaceutical compositions maycontain the present compounds in the range of about 0.1 to about 2000mg, preferably in the range of about 0.5 to about 500 mg and mostpreferably between about 1 and about 100 mg. Projected daily dosages ofactive compound are about 0.01 to about 100 mg/kg body weight. The dailydose can be conveniently administered two to four times per day.

The following non-limiting examples illustrate the preparation ofrepresentative compounds of the present invention.

The 1-aryl-3-heteroaryl-thioureas of Examples 1-19 were prepared fromsubstituted phenyl isothiocyanates by one of the following methods asindicated:

Method A: A solution (0.5 molar) of the substituted phenylisothiocyanate and an equimolar amount of the heterocyclic amine inethyl acetate was heated at reflux for 1 hour. Upon cooling, the solidsformed were filtered, washed with Et₂O and dried.

Method B: A solution (0.5 molar) of the substituted phenylisothiocyanate and an equimolar amount of the heterocyclic amine inethyl acetate was stirred overnight at ambient temperature. The solidsformed were filtered and washed with Et₂O, and dried.

Method C: An equimolar mixture of the substituted phenyl isothiocyanateand the heterocyclic amine were heated neat at 75-125° C. for 2 hours.EtOH was added and the mixture was heated at reflux for 1 hour. Whencold the solids formed were filtered, washed with Et₂O, and dried.

Method D: A solution (0.5 molar) of the substituted phenylisothiocyanate and an equimolar amount of the heterocyclic amine indioxane was heated at reflux overnight The reaction mixture wasconcentrated in vacuo to provide residual solids which were washed withEt₂O and dried.

EXAMPLE 1

1-(5-Chloro-2-methyl-phenyl)-3-(thiazol-2-yl)-thiourea

Prepared using Method C from 3.0 g (16.3 mmol) of5-chloro-2-methyl-phenyl isothiocyanate and 1.7 g (16.3 mmol) of2-amino-thiazole to give 3.58 g of title compound as a beige solid, m.p.197-198° C. (77% yield).

NMR (DMSO-d₆, 400 MHz): 2.19 (s, 3H, ArCH₃), 7.04 (broad s, 1H, ArH),7.19 (dd, 1H, ArH), 7.22 (d, 1H, ArH), 7.41 (d, 1H, ArH), 7.44 (broad,1H, ArH), 10.4 (broad, 1H, NH), 12.25 (broad, 1H, NH).

MS [EI, m/z]: 283 [M]⁺, 198, 141, 100 [b.p.]

Anal. Calc'd. for C₁₁H₁₀ClN₃S₂+0.3 mol H₂O: C, 45.68; H, 3.69; N, 14.53Found: C, 45.49; H, 3.33; N, 14.53

EXAMPLE 2

1-(Benzothiazol-2-yl)-3-(5-chloro-2-methyl-phenyl)-thiourea

Prepared using Method A from 5.0 g (27.2 mmol) of5-chloro-2-methyl-phenyl isothiocyanate and 3.90 g (26 mmol) of2-aminobenzothiazole to give 2.7 g of title compound as a white fluffysolid (30% yield).

NMR (DMSO-d₆, 400 MHz): 2.223 (s, 3H, ArCH₃), 7.25 (m, 3H, ArH), 7.40(t, 1H, ArH), 7.55 (broad s, 2H, ArH), 7.85 (broad, 1H, ArH). MultipleNH at 10.05, 11.2, 12.35, 12.9 indicate a mixture of rotamers.

MS [EI, m/z]: 333 [M]⁺, 150 [b.p.]

Anal. Calc'd. for C₁₅H₁₂ClN₃S₂: C, 53.96; H, 3.62; N, 12.59 Found: C,54.09; H, 3.48; N, 12.54

EXAMPLE 3

1-(5-Chloro-2-methyl-phenyl)-3-(naphtho[2,1-d]thiazol-2-yl)-thiourea

Prepared using Method A from 5.0 g (27.2 mmol) of5-chloro-2-methyl-phenyl isothiocyanate and 5.0 g (25 mmol) of2-amino-naptho[2,1-d]thiazole to give 2.1 g of title compound as anoff-white solid, (21% yield).

NMR (DMSO-d₆, 400 MHz): 2.27 (s, 3H, ArCH₃), 7.34 (m, 2H, ArH), 7.64 (m,3H, ArH), 7.82 (d, 1H, ArH), 8.02 (d, 2H, ArH), 8.51 (m, 1H, ArH), 10.8(broad, 1H, NH), 12.42 (broad, 1H, NH).

MS [EI, m/z]: 383 [M]⁺, 349, 242, 200 [b.p.]

Anal. Calc'd. for C₁₉H₁₄ClN₃S₂: C, 59.44; H, 3.68; N, 10.94 Found: C,59.26; H, 3.44; N, 10.95

EXAMPLE 4

1-(5-Chloro-2-methyl-phenyl)-3-(4-methyl-oxazol-2-yl)-thiourea

Prepared using Method A from 10.0 g (54.5 mmol) of5-chloro-2-methyl-phenyl isothiocyanate and 5.39 g (55 mmol) of4-methyl-2-amino-oxazole to give 8.3 g of title compound as a yellowsolid, m.p. 207-208° C. An additional crop (4.8 g, m.p. 207-208° C.) wasobtained from the mother liquor (86% combined yield).

NMR (DMSO-d₆, 400 MHz): 2.133 (s, 3H, ArCH₃), 2.439 (m, 3H, ArCH₃), 7.26(m, 3H, ArH), 7.38 (s, 2H, ArH+NH), 10.476 (s, 1H, NH).

MS [EI, m/z]: 281 [M]⁺, 266, 141 [b.p.]

Anal. Calc'd. for C₁₂H₁₂ClN₃OS: C, 51.15; H, 4.29; N, 14.91 Found: C,50.86; H, 4.10; N, 14.91

EXAMPLE 5

1-(5-Chloro-2-methyl-phenyl)-3-(5-methyl-[1,3,4]thiadiazol-2-yl)-thiourea

Prepared using Method D from 4.5 g (24.5 mmol) of5-chloro-2-methyl-phenyl isothiocyanate and 2.82 g (24.5 mmol) of5-amino-2-methyl-[1,3,4]thiadiazole to give 2.2 g of solids. Pure titlecompound was obtained by trituration of the crude solid with 1N HCl. Thesolids were collected, washed with H₂O, EtOAc and dried under highvacuum to give 2.1 g of the title compound as a white solid (29% yield,m.p. sinters 190° C., melts >250° C.).

NMR (DMSO-d₆, 400 MHz): 2.15 (s, 3H, ArCH₃), 2.47 (s, 3H, ArCH₃), 7.20(d, 1H, ArH), 7.26 (d, 1H, ArH), 7.36 (broad s, 1H, ArH), 10.02 (s, 1H,NH), 13.75 (broad, 1H, NH).

MS [EI, m/z]: 298 [M]⁺, 265, 115 [b.p.]

EXAMPLE 6

1-(5-Chloro-2-methyl-phenyl)-3-(1-methyl-1H-pyrazol-3-yl)-thiourea

Prepared using Method A from 4.73 g (27.5 mmol) of5-chloro-2-methyl-phenyl isothiocyanate and 2.5 g (25.7 mmol) of1-methyl-3-aminopyrazole to give 6.8 g of title compound as a whitesolid (95% yield, m.p. 217-218° C.).

NMR (DMSO-d₆, 400 MHz): 2.25 (s, 3H, ArCH₃), 3.78 (m, 3H, ArCH₃), 5.975(s, 1H, ArH), 7.195 (dd, 1H, ArH), 7.28 (d, 1H, ArH), 7.66 (d, 1H, ArH),7.955 (d, 1H, ArH), 10.8 (s, 1H, NH), 11.35 (broad, 1H, NH).

MS [EI, m/z]: 280 [M]⁺, 265, 247, 197, 97 [b.p.]

Anal. Calc'd. for C₁₂H₁₃ClN₄S: C, 51.33; H, 4.67; N, 19.95 Found: C,51.13; H, 4.51; N, 19.95

EXAMPLE 7

1-(5-Chloro-2-methyl-phenyl)-3-(1H-pyrazol-3-yl)-thiourea

Prepared using Method A from 5.5 g (30.1 mmol) of5-chloro-2-methyl-phenyl isothiocyanate and 2.5 g (30.1 mmol) of3-amino-1H-pyrazole to give 5.3 g of title compound as a white solid(66% yield, m.p. 221-222° C.).

NMR (DMSO-d₆, 400 MHz): (major tautomer): 2.235 (s, 3H, ArCH₃), 6.01 (s,1H, ArH), 7.20 (d, 1H, ArH), 7.28 (d, 1H, ArH), 7.72 (s, 1H, ArH), 7.91(s, 1H, ArH), 10.84 (s, 1H, NH), 11.5 (broad, 1H, NH), 12.66 (s, 1H,NH).

(minor tautomer): 2.16 (s, 3H, ArCH₃), 5.68 (s, 1H, ArH), 5.95 (d, 1H,ArH), 7.28 (d, 1H, ArH), 7.41 (d, 1H, ArH), 8.36 (d, 1H, ArH), 10.79 (s,1H, NH), 11.5 (broad, 1H, NH), 12.66 (s, 1H, NH).

MS [EI, m/z]: 266 [M]⁺, 251, 233, 183, 83 [b.p.]

Anal. Calc'd. for C₁₁H₁₁ClN₄S : C, 49.63; H, 4.16; N, 21.00 Found: C,49.55; H, 4.06; N, 21.20

EXAMPLE 8

1-(5-Chloro-2-methyl-phenyl)-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-thiourea

Prepared using Method A from 4.5 g (24.5 mmol) of5-chloro-2-methyl-phenyl isothiocyanate and 3.06 g (24.5 mmol) of4-amino-1,3,5-trimethylpyrazole to give 5.4 g of title compound as awhite solid, m.p. 176-177° C. (71% yield).

NMR (DMSO-d₆, 400 MHz): 2.02 (s, 3H, ArCH₃), 2.094 (broad s, 6H, ArCH₃),3.61 (s, 3H, NCH₃), 7.05 (broad s, 1H, ArH), 7.08 (s, 2H, ArH), 8.57(broad, 1H, NH), 9.14 (broad, 1H, NH).

MS [EI, m/z]: 308 [M⁺, b.p.], 275, 167, 142, 125.

Anal. Calc'd. for C₁₄H₁₇ClN₄S: C, 54.45; H, 5.55; N, 18.14 Found: C,54.23; H, 5.58; N, 18.06

EXAMPLE 9

1-(5-Chloro-2-methyl-phenyl)-3-(4-methyl-thiazol-2-yl)-thiourea

Prepared using Method B from 4.5 g (24.5 mmol) of5-chloro-2-methyl-phenyl isothiocyanate and 2.8 g (24.5 mmol) of2-amino-4-methylthiazole to give 4.8 g of title compound as an off-whitesolid (95% yield, m.p. 188° C.).

NMR (DMSO-d₆, 400 MHz): 2.19 (s, 6H, ArCH₃), 6.58 (broad, 1H, ArH), 7.18(dd, 1H, ArH), 7.26 (d, 1H, ArH), 7.605 (broad, 1H, ArH), 10.0 (verybroad 1H, NH), 12.24 (broad, 1H, NH).

MS [EI, m/z]: 297 [M]⁺, 114 [b.p.]

Anal. Calc'd. for C₁₂H₁₂ClN₃S₂: C, 48.39; H, 4.06; N, 14.11 Found: C,48.18; H, 3.88; N, 14.08

EXAMPLE 10

1-(5-Chloro-2-methyl-phenyl)-3-(4,5-dimethyl-thiazol-2-yl)-thiourea

Prepared using Method B from 4.5 g (24.5 mmol) of5-chloro-2-methyl-phenyl isothiocyanate and 2.79 g (24.5 mmol) of2-amino-4,5-dimethylthiazole to give 2.4 g of title compound as a whitesolid (31% yield, m.p. 188-189° C.).

NMR (DMSO-d₆, 400 MHz): 2.092 (s, 3H, ArCH₃), 2.15 (s, 3H, ArCH₃), 2.17(s, 3H, ArCH₃), 7.16 (dd, 1H, ArH), 7.24 (d, 1H, ArH), 7.15 (broad, 1H,ArH), 9.5 (broad, 1H, NH), 12.13 (broad, 1H, NH).

MS [EI, m/z]: 311 [M]⁺, 171, 128 [b.p.]

Anal. Calc'd. for C₁₃H₁₄ClN₃S₂: C, 50.07; H, 4.53; N, 13.47 Found: C,49.70; H, 4.32; N, 13.45

EXAMPLE 11

{2-[3-(5-Chloro-2-methyl-phenyl)-thioureido]-thiazol-4-yl}-acetic acidethyl ester

Prepared using Method B from 4.5 g (24.5 mmol) of5-chloro-2-methyl-phenyl isothiocyanate and 4.56 g (24.5 mmol) of2-(2-amino-thiazol-4-yl)-acetic acid ethyl ester to give 3.62 g of titlecompound as a white solid (40% yield, m.p. 177-179° C.).

NMR (DMSO-d₆, 400 MHz): 1.53 (t, 3H, OCH₂CH₃), 2.191 (s, 3H, ArCH₃),3.691 (s, 2H, CH₂CO), 4.06 (q, 2H, OCH₂CH₃), 6.92 (broad, 1H, ArH), 7.21(dd,

1H, ArH), 7.28 (d, 1H, ArH), 7.74 (broad, 1H, ArH), 9.5 (broad, 1H, NH),12.1 (broad, 1H, NH).

MS [EI, m/z]: 369 [M]⁺, 186 [b.p.]

Anal. Calc'd. for C₁₅H₁₆ClN₃O₂S₂: C, 48.71; H, 4.36; N, 11.36 Found: C,48.59; H, 4.45; N, 11.30

EXAMPLE 12

1-(5-Chloro-2-methyl-phenyl)-3-(3-methyl-isothiazol-5-yl)-thiourea

Prepared using Method B from 4.5 g (24.5 mmol) of5-chloro-2-methyl-phenyl isothiocyanate and 2.8 g (24.5 mmol) of5-amino-2-methylisothiazole to give 3.3 g of title compound as anoff-white solid (45% yield, m.p. 187-188° C. with decomposition).

NMR (DMSO-d₆, 400 MHz): 2.17 (s, 3H, ArCH₃), 2.28 (s, 3H, ArCH₃), 6.82(s, 1H, ArH), 7.26 (m, 2H, ArH), 7.445 (d, 1H, ArH), 9.72 (broad s, 1H,NH), 11.59 (broad, 1H, NH).

MS [EI, m/z]: 297 [M]⁺, 263, 256, 215, 184, 151, 114 [b.p.]

Anal. Calc'd. for C₁₂H₁₂ClN₃S₂: C, 48.39; H, 4.06; N, 14.11 Found: C,48.06; H, 4.03; N, 13.94

EXAMPLE 13

1-(5-Chloro-2-methyl-phenyl)-3-(2-methyl-benzothiazol-5-yl)-thiourea

Prepared using Method A from 4.5 g (24.5 mmol) of5-chloro-2-methyl-phenyl isothiocyanate and 4.02 g (24.5 mmol) of5-amino-2-methylbenzothiazole to give 6.0 g of crude material. Soxhletextraction with EtOAc gave 2.5 g of pure title compound as a tan solid(29% yield, m.p. 173-174° C. ).

NMR (DMSO-d₆, 400 MHz): 2.22 (s, 3H, ArCH₃), 2.781 (s, 3H, ArCH₃), 7.21(dd, 1H, ArH), 7.26 (d, 1H, ArH), 7.385 (s, 1H, ArH), 7.43 (m, 1H, ArH),7.95 (d, 1H, ArH), 8.05 (d, 1H, ArH), 9.439 (s, 1H, NH), 10.002 (s, 1H,NH).

MS [EI, m/z]: 347 [M]⁺, 313 [b.p.]

Anal. Calc'd. for C₁₆H₁₄ClN₃S₂+0.03 mol EtOAc: C, 55.24; H, 4.09; N,11.99 Found: C, 55.11; H, 4.00; N, 11.92

EXAMPLE 14

1-(5-Chloro-2-methyl-phenyl)-3-(5-ethyl-[1,3,4]thiadiazol-2-yl)-thiourea

Prepared using Method D from 4.5 g (24.5 mmol) of5-chloro-2-methyl-phenyl isothiocyanate and 3.16 g (24.5 mmol) of5-amino-2-ethyl-[1,3,4]thiadiazole to give 3.0 g of residual solids.Pure title compound was obtained by trituration of the crude solid with1N HCl. The solids were collected, washed with H₂O, EtOAc and driedunder high vacuum to give 2.55 g of the title compound as a white solid(34% yield, m.p. sinters 170° C., melts 231-233° C. with decomposition).

NMR (DMSO-d₆, 400 MHz): 1.24 (t, 3H, CH₂CH₃), 2.152 (s, 3H, ArCH₃), 2.84(q, 2H, CH₂CH₃), 7.20 (dd, 1H, ArH), 7.26 (d, 1H, ArH), 7.34 (s, 1H,ArH), 10.04 (s, 1H, NH), 13.5 (broad, 1H, NH).

MS [EI, m/z]: 312 [M]⁺, 279, 129 [b.p.]

Anal. Calc'd. for C₁₂H₁₃ClN₄S₂: C, 46.07; H, 4.19; N, 17.19 Found: C,46.21; H, 4.13; N, 17.99

EXAMPLE 15

1-(2-Chloro-6-methyl-phenyl)-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-thiourea

Prepared using Method A from 4.0 g (21.8 mmol) of2-chloro-6-methyl-phenyl isothiocyanate and 2.7 g (21.8 mmol) of4-amino-1,3,5-trimethylpyrazole to give 4.5 g of title compound as awhite solid (67% yield, m.p. 201-202° C.).

NMR (DMSO-d₆, 400 MHz): 2.05 (broad s, 3H, ArCH₃), 2.12 (broad s, 3H,ArCH₃), 2.16 (broad s, 3H, ArCH₃), 3.61 (s, 3H, NCH₃), 7.16 (broad s,2H, ArH), 7.27 (broad s, 1H, ArH), 8.44 (broad, 1H, NH), 9.13 (broad,1H, NH).

MS [EI, m/z]: 308 [M]⁺, 273 [b.p.]

Anal. Calc'd. for C₁₄H₁₇ClN₄S: C, 54.45; H, 5.55; N, 18.14 Found: C,54.25; H, 5.30; N, 17.92

EXAMPLE 16

1-(4-Chloro-2-methyl-phenyl)-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-thiourea0.12 solvate with acetic acid ethyl ester

Prepared using Method A from 4.0 g (21.8 mmol) of4-chloro-2-methyl-phenyl isothiocyanate and 2.7 g (21.8 mmol) of4-amino-1,3,5-trimethylpyrazole to give 5.5 g of title compound as awhite solid (82% yield, m.p. 178° C.).

NMR (DMSO-d₆, 400 MHz): 2.02 (broad s, 3H, ArCH₃), 2.08 (broad s, 3H,ArCH₃), 2.11 (broad s, 3H, ArCH₃), 3.32 (s, 3H, NCH₃), 7.02 (broad s,1H, ArH), 7.19 (s, 1H, ArH), 7.27 (broad s, 1H ArH), 8.52 (broad, 1H,NH), 9.13 (broad, 1H, NH).

MS [EI, m/z]: 308 [M⁺, b.p.], 275.

Anal. Calc'd. for C₁₄H₁₇ClN₄S+0.12 mol EtOAc: C, 54.45; H, 5.65; N,17.64 Found: C, 54.32; H, 5.52; N, 17.62

EXAMPLE 17

1-(4-Chloro-2-methyl-phenyl)-3-(4-methyl-oxazol-2-yl)-thiourea

Prepared using Method A from 4.04 g (22 mmol) of4-chloro-2-methyl-phenyl isothiocyanate and 2.16 g (22 mmol) of2-amino-4-methyloxazole to give 4.5 g of crude title compound. Puretitle compound was obtained by flash chromatography (silica Merck 60,CH₂Cl₂-CH₃OH, 19:1) and crystallization from CH₃CN to give 2.12 g of thetitle compound as a yellow solid (72.5% yield, m.p. 214° C. withdecomposition).

NMR (DMSO-d₆, 400 MHz): 2.14 (s, 3H, ArCH₃), 2.43 (s, 3H, ArCH₃), 7.17(d, 1H, ArH), 7.26 (dd, 1H, ArH), 7.36 (m, 3H, ArH+NH), 10.45 (s, 1H,NH).

MS [EI, m/z]: 281 [M]⁺, 256, 248, 141 [b.p.]

Anal. Calc'd. for C₁₂H₁₂ClN₃OS: C, 51.15; H, 4.29; N, 14.91 Found: C,50.87; H, 4.10; N, 14.76

EXAMPLE 18

1-(2-Chloro-6-methyl-phenyl)-3-(4-methyl-oxazol-2-yl)-thiourea

Prepared using Method A from 4.04 g (22 mmol) of2-chloro-6-methyl-phenyl isothiocyanate and 2.16 g (22 mmol) of2-amino-4-methyloxazole to give 2.4 g of an amber oil. Crystallizationfrom CH₃CN afforded 2.4 g of the title compound as a yellow solid (39%yield, m.p. 222° C. with decomposition).

NMR (DMSO-d₆, 400 MHz): 2.167 (s, 3H, ArCH₃), 2.434 (s, 3H, ArCH₃),7.239 (m, 2H, ArH), 7.32-7.4 (m, 3H, ArH+NH), 10.4 (s, 1H, NH).

MS [+FAB, m/z]: 282 [M+H]⁺

EXAMPLE 19

3-(5-Chloro-2-methyl-phenyl)-1-ethyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-thiourea

Step A: 4-Acetamido-1,3,5-trimethyl-1H-pyrazole

Under anhydrous conditions, a mixture of4-amino-1,3,5-trimethyl-1H-pyrazole (10 g, 80 mmol) and triethylamine(16.7 mL, 120 mmol) was treated dropwise with acetyl chloride (6.3 mL,88 mmol). The reaction mixture was stirred at ambient temperature for 72hours. The triethylamine hydrochloride was removed by vacuum filtration.The filtrate was concentrated in vacuo and the residue triturated withEt₂O to give 9.6 g of title compound as a tan solid (72% yield, m.p.118-119° C.).

NMR (DMSO-d₆, 400 MHz): 1.916 (s, 3H, COCH₃), 1.9446 (s, 3H, ArCH₃),2.003 (s, 3H, ArCH₃), 3.5879 (s, 3H, NCH₃)

MS (EI, m/z): 167 [M]⁺

Step B: 4-Ethylamino-1,3,5-trimethyl-1H-pyrazole

Under an atmosphere of nitrogen, lithium aluminum hydride, LAH, (4.3 g,113.6 mmol) was added portionwise to a vigorously stirred solution of4-acetamido-1,3,5-trimethyl-1H-pyrazole (9.5 g, 56.8 mmol) of step A.After stirring at ambient temperature for 2 hours, the mixture washeated at reflux for 1 hour and the excess LAH was decomposed by thecareful addition of 4.3 mL of H₂O, 4.3 mL of 1N NaOH, 12.9 mL of H₂O and54 g Na₂SO₄. The solids were filtered and the filtrate concentrated invacuo to give 7.26 g of title compound as a brown oil (91% crude yield).

NMR (DMSO-d₆, 400 MHz): 0.97 (t, 3H, CH₂CH₃), 1.98 (s, 3H, ArCH₃), 2.06(s, 3H, ArCH₃), 2.72 (q, 2H, CH₂CH₃), 3.536 (s, 3H, NCH₃)

MS (EI, m/z): 153 [M]⁺

Step C:3-(5-Chloro-2-methyl-phenyl)-1-ethyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-thiourea

Prepared using Method A from 9.33 g (51 mmol) of5-chloro-2-methyl-phenyl isothiocyanate and4-ethylamino-1,3,5-trimethylpyrazole (7.2 g, 47 mmol) of step B to give5.4 g of title compound as a white solid (70% yield, m.p. 144-145° C.).NMR (DMSO-d₆, 400 MHz): 1.07 (t, 3H, CH₂CH₃), 2.04 (s, 3H, ArCH₃), 2.07(s, 3H, ArCH₃), 2.11 (s, 3H, ArCH₃), 3.82 (s, 3H, NCH₃), 4.23 (m, 2H,CH₂CH₃), 7.02 (s, 1H, ArH), 7.19, (s, 2H, ArH), 8.41 (s, 1H, NH).

MS [EI, m/z]: 336 [M]⁺, 195 [b.p.]

Anal. Calc'd. for C₁₆H₂₁ClN₄S: C, 57.04; H, 6.28; N, 16.63 Found: C,56.93; H, 6.18; N, 16.44

The substituted 1-aryl-3-heteroaryl isothioureas of Examples 20-21 wereprepared as follows:

EXAMPLE 20

(E)-1-(5-Chloro-2-methyl-phenyl)-2-methyl-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-isothiourea

Under anhydrous conditions, a solution of1-(5-Chloro-2-methyl-phenyl)-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-thiourea(2.3 g, 7.5 mmol) produced in example 8 and methyl iodide (0.94 mL, 15mmol) in 70 mL of acetone was stirred at ambient temperature for 64hours. The reaction mixture was concentrated in vacuo and partitionedbetween CH₂Cl₂ and saturated aqueous NaHCO₃ solution. The organic phasewas washed with dilute Na₂S₂O₃ and dried (Na₂SO₄). Removal of solventand crystallization of the residue from Et₂O provided 1.78 g of titlecompound as a white solid (74% of theory, m.p. 134-135° C.).

NMR (DMSO-d₆, 400 MHz): 1.97 (s, 3H, ArCH₃), 2.03 (s, 3H, ArCH₃), 2.06(s, 3H, ArCH₃), 2.29 (s, 3H, SCH₃), 3.60 (s, 3H, NCH₃), 6.678 (s, 1H,ArH), 6.87 (dd, 1H, ArH), 7.12 (d, 1H, ArH), 7.45 (s,1H, NH).

MS (+FAB, m/z): 323 [M+H]⁺

Anal. Calc'd for C₁₅H₁₉ClN₄S: C, 55.80; H, 5.93; N, 17.35 Found: C,55.70; H, 5.88; N, 17.36

EXAMPLE 21

3-(5-Chloro-2-methyl-phenyl)-1-ethyl-2-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-isothiourea1:1 salt with hydrochloric acid

A mixture of3-(5-Chloro-2-methyl-phenyl)-1-ethyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-thiourea(6.2 g, 19.1 mmol) of example 19, methyl iodide (2.4 mL, 38.3 mmol), andpotassium carbonate (5.24 g, 38 mmol) in 100 mL of acetone was heated atreflux for 7 hours. The solids were filtered washed with EtOAc and thefiltrate concentrated in vacuo. The removal of solvent in vacuo providedthe title compound as a clear oil (6.2 g, 92% of theory). Thehydrochloride salt was prepared by treating an ethereal solution of thetitle compound with 20 mL of 1N HCl in Et₂O. The salt was filtered anddried under high vacuum to provide the title compound as a white solid(3.2 g, 43% of theory, m.p. 158° C. with decomposition).

NMR (DMSO-d₆, 400 MHz): 1.102 (t, 3H, CH₂CH₃), 1.9 (s, 3H, ArCH₃), 2.03(broad s, 3H, ArCH₃), 2.118 (broad s, 3H, ArCH₃), 2.16 (s, 3H, SCH₃),3.619 (broad s, 3H, NCH₃), 3.79 (broad, 2H, CH₂CH₃), 7.12 (broad, 2H,ArH), 7.22 (d, 1H, ArH).

MS [EI, m/z]: 350 [M]⁺, 152 [b.p.]

Anal. Calc'd. for C₁₇H₂₃ClN₄S.HCl: C, 52.71; H, 6.24; N, 14.46 Found: C,52.46; H, 6.16; N, 14.53

The present invention may be embodied in other specific forms withoutdeparting from the spirit and essential attributes thereof andaccordingly, reference should be made to the appended claims, ratherthan to the foregoing specification, as indicating the scope of theinvention.

What is claimed is:
 1. An antiatherosclerotic agent represented byFormulas I or II:

wherein R is

wherein R₉, R₁₀, R₁₁R₁₂, R₁₃, and R₁₄ are each, independently, hydrogenor a lower alkyl of 1-6 carbon atoms; R₆, and R₇ are each,independently, hydrogen, lower alkyl of 1-6 carbon atoms, or CH₂COOR₈,where R₈ is a lower alkyl of 1-6 carbon atoms; and X is O or S; R₁ ishydrogen or a lower alkyl of 1-6 carbon atoms; R₂, R₃, and R₄ are each,independently, hydrogen or halogen, with the proviso that at least oneof R₂, R₃, and R₄ must be halogen; and R₅ is a lower alkyl of 1-6 carbonatoms; or a pharmaceutically acceptable salt thereof.
 2. Theantiatherosclerotic agent of claim 1, wherein: R is

wherein: R₉, R₁₀, R₁₁, R₁₂, R₁₃, and R₁₄ are each, independently,hydrogen or lower alkyl of 1 to 6 carbon atoms; R₆ and R₇ are, eachindependently, lower alkyl of 1 to 6 carbon atoms; and X is O or S; R₁is hydrogen; R₂, R₃, and R₄ are each, independently, hydrogen orhalogen, with the proviso that at least one of R₂, R₃ and R₄ must behalogen: and R₅ is a lower alkyl of 1 to 6 carbon atoms; or apharmaceutically acceptable salt thereof.
 3. The antiatheroscleroticagent of claim 1, which is1-(5-chloro-2-methyl-phenyl)-3-(thiazol-2-yl)-thiourea.
 4. Theantiatherosclerotic agent of claim 1, which is1-(5-chloro-2-methyl-phenyl)-3-(4-methyl-oxazol-2-yl)-thiourea.
 5. Theantiatherosclerotic agent of claim 1, which is1-(5-chloro-2-methyl-phenyl)-3-(4-methyl-thiazol-2-yl)-thiourea.
 6. Theantiatherosclerotic agent of claim 1, which is1-(5-chloro-2-methyl-phenyl)-3-(4,5-dimethyl-thiazol-2-yl)thiourea. 7.The antiatherosclerotic agent of claim 1, which is{2-[3-(5-chloro-2-methyl-phenyl)-thioureido]-thiazol-4-yl}-acetic acidethyl ester.
 8. The antiatherosclerotic agent of claim 1, which is1-(4-chloro-2-methyl-phenyl)-3-(4-methyl-oxazol-2-yl)-thiourea.
 9. Theantiatherosclerotic agent of claim 1, which is1-(2-chloro-6-methyl-phenyl)-3-(4-methyl-oxazol-2-yl)-thiourea.